Post-transcriptional modifications (PTMs) of histones affect gene transcription
https://reasonandscience.catsboard.com/t2727-post-transcriptional-modifications-ptms-of-histones-affect-gene-transcription
1. A codified information transmission system depends on: a) A code as a system of rules where a symbol, letters, words, or even sounds, gestures, or images, are assigned to something else. Assigning meaning of characters through a code system requires a common agreement of meaning. Statistics, Semantics, Synthax, Pragmatics, and Apobetics b) Information encoded through that code, c) An information storage system, and d) an information transmission system, that is encoding, transmitting, and decoding.
2. We see that precisely in eukaryotic cells, where information is encoded through the histone code which is a set of rules, stored in amino acid sequences in the histone tail. They are used to orchestrate gene expression. The assignment of codified meaning to combinatorial amino acid sequences must be pre-established by a mind. And so, the information which is sent through the system, as well as the communication channels that permit encoding, sending, and decoding, which in gene expression is done through the orchestration of histone code readers, writers, erasers, and permit the loosening and tightening chromatin, and in consequence, the RNA polymerase machinery to express specific genes. This system had to be set up all at once. That is the software - the histone code "language", as well as the hardware, that is the histone tails upon which the "message" is written, the readers, writers, and erasers.
3. The origin of such complex communication systems is best explained by an intelligent designer. Since no humans were involved in creating these complex computing systems, a suprahuman super-intelligent agency must have been the creator.
The histone Information system is irreducibly complex
1. In living cells, information is encoded through the histone code which is a set of rules, stored in amino acid sequences in the histone tail. They are used to orchestrate gene expression. And so, the information which is sent through the system, as well as the communication channels that permit encoding, sending, and decoding, which in gene expression is done through the orchestration of histone code readers, writers, erasers, and permit the loosening and tightening chromatin, and in consequence, the RNA polymerase machinery to express specific genes.
2. A codified information transmission system depends on: a) A code as a system of rules where a symbol, letters, words, or even sounds, gestures, or images, are assigned to something else. Assigning meaning of characters through a code system requires a common agreement of meaning. Statistics, Semantics, Synthax, and Pragmatics, b) Information encoded through that code, c) An information storage system, and d) an information transmission system, that is encoding, transmitting, and decoding.This system had to be set-up all at once. That is the software - the histone code "language", as well as the hardware, that is the histone tails upon which the "message" is written, the readers, writers, and erasers.
3. The assignment of codified meaning to combinatorial amino acid sequences must be pre-established by a mind.The origin of such complex communication systems is best explained by an intelligent designer. Since no humans were involved in creating these complex computing systems, a suprahuman super-intelligent agency must have been the creator.
Loosening and tightening chromatin: Histones as gatekeepers
Histones are critical because they are responsible for either facilitating or forbidding gene expression.
Methyl groups condense nucleosomes more tightly, preventing access to promoter sites and thus preventing gene transcription. Acetylation loosens nucleosome packing, exposing the DNA to RNA polymerase II and transcription factors that will activate the genes.
Repression and activation are controlled to a large extent by modifying the “tails” of histones H3 and H4 with two small organic groups: methyl (CH3) and acetyl (COCH3) residues. In general, histone acetylation— the addition of negatively charged acetyl groups to histones—neutralizes the basic charge of lysine and loosens the histones, which activates transcription. Enzymes known as histone acetyltransferases place acetyl groups on histones (especially on lysines in H3 and H4), destabilizing the nucleosomes so that they come apart easily (become more euchromatic). As might be expected, then, enzymes that remove acetyl groups—histone deacetylases—stabilize the nucleosomes (which become more heterochromatic) and prevent transcription.
Histone methylation is the addition of methyl groups to histones by enzymes called histone methyltransferases. Although histone methylation more often results in heterochromatic states and transcriptional repression, it can also activate transcription depending on the amino acid being methylated and the presence of other methyl or acetyl groups in the vicinity. For instance, acetylation of the tails of H3 and H4 along with the addition of three methyl groups on the lysine at position four of H3 (i.e., H3K4me3; remember that K is the abbreviation for lysine) is usually associated with actively transcribed chromatin. In contrast, a combined lack of acetylation of the H3 and H4 tails and methylation of the lysine in the ninth position of H3 (H3K9) is usually associated with highly repressed chromatin. Indeed, lysine methylations at H3K9, H3K27, and H4K20 are often associated with highly repressed chromatin.
Histone methylations on histone H3.
The tail of histone H3 (its aminoterminal sequence, at the beginning of the protein) sticks out from the nucleosome and is capable of being methylated or acetylated. Here, lysines can be methylated and recognized by particular proteins. Methylated lysine residues at positions 4, 38, and 79 are associated with gene activation, whereas methylated lysines at positions 9 and 27 are associated with repression. The proteins binding these sites (not shown to scale) are represented above the methyl group.
Post-transcriptional modifications (PTMs) of histones affect gene transcription
This is certainly the most relevant epigenetic level of transcription regulation. In brief, histones have “tails” that can be modified by attaching various kinds of groups to them. So, each of the four histone types in the nucleosome (usually H2A, H2B, H3 and H4) can be methylated or polymethylated, acetylated, phosphorylated, ubiquitinated, sumoylated, biotinylated and many other things, at different amino acid sites, usually lysines or arginines. The combinatorial result is that more than 150 different histone PTMs have been described. However, methylations and acetylations are the most studied. Histone H3 is the most involved in current studies, and methylations and acetylations are the modifications that have been better analyzed.. The term “histone code” refers in a general way to the sum total of these different modifications and of their effects on chromatin state and transcription. However, many aspects of these complex processes are still poorly understood. In general, the best known PTMs are classified as having an effect of transcription activation or repression. Acetylations are mostly activating, methylation can be either activating or repressing. 43
The amino-terminal tails of histone proteins are subject to several types of covalent modifications. For example, an enzyme called histone acetyltransferase attaches acetyl groups (—COCH3) to the amino-terminal tails of histone proteins. When acetylated, histone proteins do not bind as tightly to the DNA, which aids in transcription. Over 50 different enzymes have been identified in mammals that selectively modify amino-terminal tails. The figure below shows an example in the amino-terminal tails of histone proteins H2A, H2B, H3, and H4 that can be modified by acetyl, methyl, and phosphate groups.
Indeed, lysine methylations at H3K9, H3K27, and H4K20 are often associated with highly repressed chromatin. The figure above depicts a nucleosome with lysine residues on its H3 tail. Modifications of such residues regulate transcription. If methyl groups at specific places on histones repress transcription, getting rid of these methyl moieties should be expected to permit transcription. That has been shown to be the case in the activation of the Hox genes, a family of genes that are critical in giving cells their identities along the anterior-posterior body axis. In early development, Hox genes are repressed by H3K27 trimethylation (the lysine at position 27 on histone
3 has three methyl groups: H3K27me3). In differentiated cells, however, a demethylase specific for H3K27me3 is recruited to these regions, eliminating the methyl groups and enabling access to the gene for transcription. The
effects of methylation in controlling gene transcription are extensive.
Examples of covalent modifications that occur to the amino terminal tails of histone proteins.
The amino acids are numbered from the N-terminus, or amino end. The modifications shown here are m for methylation, p for phosphorylation, and ac for acetylation. Many more modifications can occur to the amino terminal
tails. These modifications are reversible.
What are the effects of covalent modifications of histones? First, modifications may directly influence interactions between DNA and histone proteins, and between adjacent nucleosomes. The acetylation of histones loosens their binding to DNA and aids in transcription. Second, histone modifications provide binding sites that are recognized by other proteins.
The histone Code hypothesis
According to the histone code hypothesis, proposed by American biologists Brian Strahl and David Allis in 2000, the pattern of histone modification is recognized by proteins much like a language or code. One pattern of histone modification may attract proteins that inhibit transcription. Alternatively, a different combination of histone modifications may attract proteins, such as ATP-dependent chromatin-remodeling complexes, that promote gene transcription. In this way, the histone code plays a key role in accessing the information within the genomes of eukaryotic species.
The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar Modifications such as DNA methylation, it is part of the epigenetic code. Histones associate with DNA to form nucleosomes, which themselves bundle to form chromatin fibers, which in turn make up the more familiar chromosome. Histones are globular proteins with a flexible N-terminus (taken to be the tail) that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlates well to gene expression levels. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. 19
Combinations of histone modifications at a given position on the genome constitute the input system, the adaptors are the epigenetic regulators (for instance enzymatic complex Ezh2) that bind the modifications and outputs are chromatin features such as the level of chromatin compaction or gene expression 38 The histone modification sequence is orchestrated by the enzymes that either deposit, read or remove the marks, and serve as the adaptors molecules essential to biological codes. Enzymes that deposit marks are diverse and reflect the large spectrum of modifications available . Well-known examples are of histone acetyl-transferases (HAT) which transfer the acetyl group from acetyl-Coenzyme A to the tail of histones, and histone deacetylases (HDACs) which remove the acetyl groups, most notably upon chromatin compaction.
The impact of three primary histone modifications on chromatin compaction.
H3K4me3-rich nucleosomes are associated with active chromatin in an open conformation, H3K27me3-rich nucleosomes are associated with repressed chromatin, while H3K9me3-rich nucleosomes are associated with highly-compacted, inactive chromatin.
It has been half a century since Vincent Allfrey first described the presence of acetylation and methylation on histones, and Lubomir Hnilica documented histone phosphorylation, the functional significance of these modifications remained elusive for many years. Fundamental breakthroughs in our understanding of histone PTM function (many of which occurred in recent years) have been made through the identification of the protein machineries that incorporate (write), remove (erase), and bind (read) histone PTMs. Two landmark discoveries in this regard were the identifications in 1996 of p55/Gcn5 and HDAC1/Rpd3 as transcription-associated histone acetyltransferases and deacetylases, respectively — thereby linking dynamic histone modification activity directly to the transcription process. These findings changed the landscape of how the transcription and chromatin fields viewed histone PTMs and have resulted in a fast-paced and exciting field that shows no signs of slowing down. In 2000, the concept of a ‘histone code’ emerged as a hypothesis to stimulate new thinking about how histone PTMs might function, like through the selective recruitment of effector proteins or readers that ‘dock’ onto histone PTMs to direct specific downstream events in chromatin. While the ‘histone code’ hypothesis provided a retrospectively simplistic explanation of how histone PTMs function, recent advances have revealed that the context in which histone PTMs operate is much more complex than originally envisioned. 39
Post-translational modifications (PTMs) of histones provide a fine-tuned mechanism for regulating chromatin structure and dynamics. 36
In addition to combinatorial PTMs that function together both synergistically and antagonistically, there is now an appreciation for PTM asymmetry within individual nucleosomes, novel types of PTMs with unique functions, nucleosomes bearing histone variants, and nuclear compartmentalization events that are all contributing to the final output of chromatin organization and function.
Histone–DNA interface PTMs (in contrast to those located on the histone tail domains) largely act in a physical manner by tweaking or fine-tuning histone–DNA interactions that in turn affect nucleosome stability and/or mobility. While PTMs located at the histone–DNA interface regulate the intrinsic properties of the nucleosome core particle, it is noteworthy that these modifications can also regulate effector protein association similar to those located in the tail domains.
Posttranslational modifications (PTMs) on histones act singly and in combination to form a language or ‘code’ that is read by specialized proteins to facilitate downstream functions in chromatin. Underappreciated at the time this was discovered in the early-2000's was the level of complexity harbored both within histone PTMs and their combinations, as well as within the proteins that read and interpret the language. In addition to histone PTMs, newly-identified DNA modifications that can recruit specific effector proteins have raised further awareness that histone PTMs operate within a broader language of epigenetic modifications to orchestrate the dynamic functions associated with chromatin.
The hypothesis is that chromatin-DNA interactions are guided by combinations of histone modifications. While it is accepted that modifications (such as methylation, acetylation, ADP-ribosylation, ubiquitination, citrullination, and phosphorylation) to histone tails alter chromatin structure, a complete understanding of the precise mechanisms by which these alterations to histone tails influence DNA-histone interactions are to be figured out. However, some specific examples have been worked out in detail. For example, phosphorylation of serine residues 10 and 28 on histone H3 is a marker for chromosomal condensation. Similarly, the combination of phosphorylation of serine residue 10 and acetylation of a lysine residue 14 on histone H3 is a tell-tale sign of active transcription.
Histone post-translational modifications (PTMs) generate a complex combinatorial code that regulates gene expression and nuclear functions, and whose deregulation has been documented in different types of cancers.
25
This raises the question: How could such a combinatorial code have evolved, if regulation is a must, and deregulation is a source of cancer and cell death?
Functional Consequences of Histone Modifications
(A) Gene-expression changes are brought about by the recruitment of the NURF complex, which contains a component BRTF recognizing H3K4me and a component-remodeling chromatin.
(B) The Crb2 protein of fission yeast is recruited to DNA-repair foci during a DNA-repair response. Crb2 is partly tethered there by association with methylated H4 and phosphorylated H2A.
(C) The HBO1 acetyltransferase is an ING5-associated factor and is therefore tethered to sites of replication via methylated H3K4. HBO1 also binds to the MCM proteins found at replication sites. Evidence exists that HBO1 augments the formation of the preinitiation complex and is required for DNA replication.
About languages, codes, and libraries
A genomic library is a collection of the total genetic information stored in DNA from a single organism. The information in a library does no good to anyone unless the books are read. The same thing is true for DNA -- without being read, it doesn't do any good. So there are some obvious parallels between a library and a cell's DNA. Each gene could be compared to one assembly manual. Genes are organized in long strings, called chromosomes. If a gene is an assembly manual, then you can think of each chromosome as a shelf in a library. All the chromosomes together are like a library full of shelves. A nucleosome is like a shelf of the library, a basic unit of DNA packaging in eukaryotes, consisting of a segment of DNA wound in sequence around eight histone protein cores. Imagine the DNA strand equivalent to the book which carries the information. It is wrapped around these globular histone proteins which form a disk, but an N-terminal histone tail is like an arm that protrudes from the nucleosome, and on that tail, information can be modified, that is: a) written, b) read, or c) erased by specific enzymes. The enzymes that write on the tail are equivalent and perform the same job as to whom informs the computer where to find the book in the shelf, inform the proteins that afterward read the information what gene section is there ( the book in our analogy ) , and as well, when the DNA wrapped around the histones has to be expressed, or remain tightly bound to histones and the transcription machinery has no access, and it is as if the book remains in the Shelf without use. These chromatin-associated proteins dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states.
The combinatorial nature of histone amino-terminal modifications thus reveals a “histone code” that orchestrates and regulates gene expression. This epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
Epigenetics, imposed at the level of DNA-packaging proteins (histones), is a critical feature of a genome-wide mechanism of information storage and retrieval. Histone proteins and their associated covalent modifications contribute to a mechanism that can alter chromatin structure, thereby leading to inherited differences in transcriptional “on-off” states or to the stable propagation of chromosomes by defining a specialized higher order structure at centromeres.
The enzymes transducing these histone tail modifications are highly specific for particular amino acid positions.
Question: How could this specificity have emerged slowly, in a gradual evolutionary manner? Trial and error? and why would unguided, non-intelligent biochemical molecules even produce such specific, highly complex information storage and retrieval systems of other information?
Epigenetic “on-off ” transcriptional states are largely dependent on the position of a gene within an accessible (euchromatic) or an inaccessible (heterochromatic) chromatin environment.
a) The human language is an advanced information and communication system and must be determined by the common agreement of meaning of words and grammar in advance before any communication can take place, understood by both, sender and receiver.
b) Information transmitted through spoken words can be expressed in written words, that is, words and sentences are transformed into a codified communication form through codes or symbols, and a system of rules which function as representation, most commonly through writing systems, like the alphabet, or Kanji etc. In order for communication to occur, a mutual understanding, both, of a) the language, and b) of the code, by the sender, and the receiver is required. The transmission of codified information occurs through communication channels. It has to be a) written b) transmitted, c) read, and d) and eventually deleted or erased if so required. The codified information can also be stored in mediums, like ink/paper, or computer hard disks etc.
there has to be a common language understood by sender and receiver
a code system able to represent the language understood by sender and receiver
a sender/encoder that transmits the information based on the language, and rules of the code
a communication channel that transmits the information, and knows how to send the information to the right destination/address.
a receiver/decoder that receives the information and understands the code, and the language.
- if an English speaker visits a German website, it won't understand the information, even if its the same message written with the alphabet, because the language is different.
- if an English speaker that only knows the alphabet visits a Japanese website providing information in the English language, but using the Japanese Kanji symbols, he won't be able to decipher the message.
- If there is an extraordinary event taking place, but nobody writes about it and publishes, nobody else will know. ( No sender )
- If there is an extraordinary event taking place, and someone reports about it, but there is no internet access to publish the information on a site on the web, nobody will be able to read it. ( No communication channel )
- If there is someone elaborating a website and publishes it on the web, but nobody knows about it, nobody will take notice. ( No receiver/reader)
A library management program is necessary for the fast retrieval and return of books. The fast retrieval of information where to find a book in a library depends on the organized labeling of each library section, shelf, and eventually even the individual books, and is ordered in theme and genre sections, and every shelf has a tag which can be recognized and informs what books are there, and what themes. The books need first to be separated by genre and put together in categories. Then they have to be cataloged, one by one, before put together to the right shelf.
So there are two hierarchical information systems in the Cell, to name: the Histone Code, which is highly complex, and functions equivalent to a code to establish a program or language equivalent / similar to a computer-based management program of a library, used by specialized histone proteins to write on histone tails and inform the histone "reader" proteins when the DNA wrapped up in the nucleosomes has to be either keep mute and silenced, or has to be expressed by the transcription machinery, and when ( the right timing ). The information written by these proteins on these tails comes from multiple sources, and depends on the programmed timing of the gene regulatory network, the development program of the organism, responses coming from signals depending on environmental conditions, and responses to food sources, and homeostasis, responses depending on feedback loops as response to needs of synthesis of basic building molecules, amino acids, nucleotides, carbohydrates, fatty acids, metabolic and catabolic responses etc.
Readers, writers, editors, and erasers
Histone protein tails are critical for controlling gene expression: they are dynamically modified by post-translational modifications (PTMs) many of the modifications have been correlated with regulatory cellular processes and chromatin structure. 30 Most histone PTMs are localized on the N-terminal tail of the histone sequence. The structure of the nucleosome leaves the N-terminal tails of the histones exposed, allowing them to be readily accessed by members of histone-related protein families.
The histone code is written on histone tails by specific enzymes, called "writers or editors", which can write ( methylate or acetylate DNA ), but not exclusively, on the histone N-terminal tail or remove information by another kind of enzymes, called "erasers", which remove modifications and have demethylase or deacetylase activity, and finally, there are proteins which can interpret and read the information, called "readers" that are recruited to such histone modifications and bind via specific domains. READERS can bind specifically to the MARK and recruit a variety of other activities. These triple action of ‘writing’, ‘reading’ and ‘erasing’ establish the favorable local environment for transcriptional regulation. 29
Readers are usually not enzymes, but proteins containing domains that recognize specific modifications, potentially recruiting complexes like transcription factors or DNA repair machinery.
it is hard to assign functions to histone modifications is their combinatorial nature; a given PTM co-exists with myriad others on the same histone protein, and it is not rare for them to be found to cross-talk with one another.
The chemical nature of histones can also be changed at the protein sequence level, where the canonical histones used to package the majority of the genome are substituted by histone variants. Although many factors, such as linker histones and DNA-binding proteins, can influence characteristics such as DNA wrapping and fiber compaction, the greatest changes in nucleosome structure and stability are achieved by histone chaperones and ATP-dependent chromatin remodelers. Histone chaperones are highly acidic proteins that stabilize histones in the absence of DNA and thus play critical roles in nucleosome assembly and disassembly. Chromatin remodelers are essential for altering the composition and position of nucleosomes by coupling ATP hydrolysis to exchange of histone variants, nucleosome sliding, and octamer assembly/disassembly.
Nucleosomes must dynamically change so that DNA binding complexes can access their binding sites. These dynamic changes, which include nucleosome unwrapping, rewrapping, sliding, assembly, and disassembly, involve the formation and/or disruption of interactions within the interfaces between the DNA, H3/H4, and H2A/H2B components of the nucleosome.
In conjunction with histone variants, PTMs not only alter the intrinsic dynamics of nucleosomes but also provide chemical signposts to help guide cellular factors to particular locations in the genome.
During mitosis, phosphorylation of threonine 3, serine 10, and serine 28 disrupts the binding of READERS to methylation MARKS on lysines 4, 9, and 28, respectively. Thus, one MARK can regulate the activity of an adjacent MARK. Acetylation involves the transfer of acetate groups from acetyl coenzyme A to the ε-amino groups of lysine. This reduces the net positive charge of the N-terminal domain, causing chromatin to adopt an “open” conformation that is more favorable to transcription. The acetylation MARK acts as a binding site for protein READERs, one example of which is an approximately 100-amino-acid sequence motif called a bromodomain. Various bromodomain-containing READERS recruited to chromatin by acetylated histones often further modify histones in other ways that either promote or limit the accessibility of the DNA for transcription into RNA.
Proteins called transcription factors regulate gene expression by binding specific DNA sequences and recruiting the transcriptional machinery (RNA polymerases and associated proteins) to activate gene expression.
NETWORK OF INTERACTIONS THAT REGULATE RNA POLYMERASE II.
Input comes from transcription factors bound to promoter proximal elements and enhancers and from coregulators that modify chromatin.
Many transcription factors recruit a protein complex, called a coactivator, that facilitates loading of the transcriptional apparatus onto the gene. Often, coactivators possess domains that recognize histone MARKS and have EDITOR activities to lay down new MARKS on N-terminal histone tails. For example, the yeast SAGA complex contains over 10 proteins, including READERS that recognize histone methylation and acetylation. It also has an EDITOR activity that removes the protein MARK ubiquitin from target proteins plus a histone acetyltransferase EDITOR activity that acetylates lysine-14 and lysine-8 in the N-terminal tails of histone H3
Transcription factors (purple) bind specific DNA sequences and recruit coactivators to the 5′ ends of genes. Many of these coactivators work by acetylating the N-terminal tails or body of the core histones, thereby loosening the chromatin structure and promoting the binding and activation of the RNA polymerase holoenzyme. The coactivators vary in composition and complexity from relatively simple histone acetyltransferase complexes (bottom left) to the huge and elaborate SAGA complex (bottom right). In this side view, only one of the two turns of DNA around the nucleosome is seen. GCN5, Ada2, Ada3, Spt3, Spt7, Spt8, and Spt20 are the names of budding yeast genes whose products are found in these complexes. AC, acetylation; TATA, DNA sequence in the gene promoter
Histone acetylation is dynamic. Just as transcriptional coactivators contain histone acetyltransferases that add acetyl groups to nucleosomes and promote gene activation, so corepressors, which are recruited in an analogous manner, can contain histone deacetylases that remove acetyl groups from selected lysine residues. Deacetylation tends to repress gene expression and is one strategy used to regulate cell-cycle progression during the G1 phase of the cell cycle. Histone acetylation is crucial for life. Yeast cells die if certain key lysines are mutated to arginines, thus preserving their positive charge but preventing them from being acetylated. In addition to marking nucleosomes by modification of their N-terminal tails, cells also use the energy provided by adenosine triphosphate (ATP) hydrolysis to actively remodel nucleosomes. This involves complex protein “machines” that include a catalytic subunit that couples ATP hydrolysis to DNA translocation. All eukaryotes possess approximately 20 different classes of these chromatin remodeling enzymes. These different subclasses are capable of directing a range of different changes to nucleosome organization. For example, some enzymes reposition nucleosomes so that they are evenly spaced along DNA. Others remove histones from DNA. Still others direct replacement of core histone proteins with specialized variants.
Post-translational modifications (PTMs) of histones provide a fine-tuned mechanism for regulating chromatin structure and dynamics. PTMs can alter direct interactions between histones and DNA and serve as docking sites for protein effectors, or readers, of these PTMs. Binding of the readers recruits or stabilizes various components of the nuclear signaling machinery at specific genomic sites, mediating fundamental DNA-templated processes, including gene transcription and DNA recombination, replication and repair. 21 The nucleosomes undergo recurrent structural rearrangements through DNA unwrapping and rewrapping and histone core disassembly and assembly, and they are subject to covalent modifications. The modifications, or epigenetic marks, have been identified on both DNA and histones. Whereas DNA can primarily be methylated, histones are capable of carrying a wide array of PTMs. A particularly large number of PTMs have been discovered on the histone tails that protrude from the nucleosomal core and are freely accessible to enzymes for the deposition or removal of PTMs.
Readers of histone PTMs. Recognition of the methylated (me) lysine, methylated (me) arginine, acetylated (ac) lysine and phosphorylated (ph) serine and threonine residues of the N-terminal histone H3 tail by indicated readers.
HISTONE MODIFICATIONS.
A, E → M → R → C pathways use posttranslational modifications to create different chromatin states.
B, Modification of the amino- and carboxyterminal domains of the histones regulates nucleosome assembly, transcription, and mitotic chromosome condensation. Highlighted here are methylations of three lysines, which are associated with transcription, heterochromatin, and facultative heterochromatin respectively. Note that each residue is immediately adjacent to a residue phosphorylated in mitosis, which knocks the READER off the methylation mark. The modifications are described in the figure key.
C, Structure of tri-methyl lysine.
A schematic depiction of a nucleosome showing principal lysine methylation sites on histones H3 and H4. The reported writers (methyltransferases) and erasers (demethylases) for each lysine methylation are also depicted with their methylation state specificities: single circle (), me1; double circle (), me2; triple circle (), me3. 37
Covalent marks on chromatin 45
(a) Chromatin consists of repeated units of 146 bp of DNA wrapped 1.7 times around an octamer composed of two copies each of the four core histones; H2a, H2b, H3 and H4. Chromatin provides a structural platform that is subject to extensive post-translational modification. These include methylation, acetylation, phosphorylation and ubiquitination of specific histone residues; methylation of CpG dinucleotides; exchange of histones
(b) changes in the relative position of the nucleosome-mediated byATP-dependent remodelling complexes
(c) induction of double-stranded DNA breaks by topoisomerase II
(d) the generation of single-stranded DNA breaks by topoisomerase I
41
A structurally diverse family of histone reader domains has been discovered over the last decade, including bromodomains that bind acetyllysine, chromodomains that bind methyllysine, plant homeodomain (PHD) fingers that bind acetyllysine, methyllysine, and even unmodified lysine, Tudor domains that bind methyllysine and methylarginine, and BRCT domains that bind phosphoserine
1 https://en.wikipedia.org/wiki/Transcription_(biology)
2. Gene Regulatory Networks: Methods and Protocols [1 ed.] page 3
3. https://en.wikipedia.org/wiki/Transcriptional_regulation
4. https://en.wikipedia.org/wiki/Transcription_factor
5. https://en.wikipedia.org/wiki/Gene_regulatory_network
6. http://sci-hub.tw/https://www.cell.com/trends/genetics/abstract/S0168-9525(17)30070-7
7. https://pdfs.semanticscholar.org/presentation/12fc/722fe7ba63bdb7a7e6fe98d395840d0fe1cf.pdf
8. Gene Regulatory Networks, Methods and Protocols, page 3
9. A Handbook of Transcription Factors (Subcellular Biochemistry ) page 2
10. https://www.annualreviews.org/doi/abs/10.1146/annurev-genom-091212-153423
11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664230/
12. https://www.semanticscholar.org/paper/Movie-script-markup-language-Rijsselbergen-Keer/ff7e21d640d1ad6c7e5b44196153ea9e01db043c
13. http://sci-hub.tw/https://www.nature.com/articles/nrg2499
14. https://en.wikipedia.org/wiki/Regulation_of_gene_expression
15. https://www.ncbi.nlm.nih.gov/pubmed/10064544
15. https://upload.wikimedia.org/wikipedia/commons/1/17/Cell_Biology.pdf
16. http://wwf.panda.org/knowledge_hub/teacher_resources/webfieldtrips/hab_adaptation/
17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091299/
18. http://sci-hub.tw/https://www.nature.com/articles/nrg2540
19. https://en.wikipedia.org/wiki/Histone_code
20. http://sci-hub.tw/https://www.nature.com/articles/nsmb.2669
21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645987/
22. http://sci-hub.tw/https://www.ncbi.nlm.nih.gov/pubmed/10638745/
23. https://en.wikipedia.org/wiki/Histone
24. https://www.nature.com/scitable/topic/gene-expression-and-regulation-15
25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934616/
26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3193420/
27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380191/
28. Xhemalce B, Dawson MA, Bannister AJ. Histone modificationsIn: Meyers R, ed. Encyclopedia of Molecular Cell Biology and Molecular Medicine. John Wiley and Sons; 2011, page 419
29. https://en.wikipedia.org/wiki/Chromatin_remodeling
30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512434/
31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323801/
32. http://sci-hub.tw/https://www.nature.com/articles/s41586-018-0029-y
33. http://sci-hub.tw/https://www.ncbi.nlm.nih.gov/pubmed/29643506
34. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947954/
35. https://www.med.unc.edu/~bstrahl/Scott%20B.%20Rothbart%20&%20Brian%20D.%20Strahl.pdf
36. http://sci-hub.tw/https://www.nature.com/articles/nsmb.2436
37. https://www.nature.com/articles/emm201711
38. https://www.biorxiv.org/content/biorxiv/early/2017/11/20/217190.full.pdf
39. https://www.roswellpark.org/sites/default/files/tomasi_paper_2_rothbart_strahl_bba_2014_interpreting_the_language_of_histone_dna_modifications.pdf
40. https://www.quora.com/Why-does-DNA-methylation-and-histone-modifications-form-the-epigenetic-code
41. https://watermark.silverchair.com/gkw1011.pdf
42. https://docs.abcam.com/pdf/chromatin/a-guide-to-epigenetics.pdf
43. https://uncommondescent.com/intelligent-design/transcription-regulation-a-miracle-of-engineering/
44. http://sci-hub.tw/https://www.ncbi.nlm.nih.gov/pubmed/16751179
45. http://sci-hub.tw/https://www.ncbi.nlm.nih.gov/pubmed/18805503/
Histone modifications - the most significant reversible factors for cell differentiation and biodiversity
https://sciencerefutesevolution.blogspot.com/2018/11/histone-modifications-most-significant.html?fbclid=IwAR0kcyhvxBNf-BvF51qE1tpkdpiPL2SsYoY-MaHtnQbukEENn_WPw7BGOD8
https://reasonandscience.catsboard.com/t2727-post-transcriptional-modifications-ptms-of-histones-affect-gene-transcription
1. A codified information transmission system depends on: a) A code as a system of rules where a symbol, letters, words, or even sounds, gestures, or images, are assigned to something else. Assigning meaning of characters through a code system requires a common agreement of meaning. Statistics, Semantics, Synthax, Pragmatics, and Apobetics b) Information encoded through that code, c) An information storage system, and d) an information transmission system, that is encoding, transmitting, and decoding.
2. We see that precisely in eukaryotic cells, where information is encoded through the histone code which is a set of rules, stored in amino acid sequences in the histone tail. They are used to orchestrate gene expression. The assignment of codified meaning to combinatorial amino acid sequences must be pre-established by a mind. And so, the information which is sent through the system, as well as the communication channels that permit encoding, sending, and decoding, which in gene expression is done through the orchestration of histone code readers, writers, erasers, and permit the loosening and tightening chromatin, and in consequence, the RNA polymerase machinery to express specific genes. This system had to be set up all at once. That is the software - the histone code "language", as well as the hardware, that is the histone tails upon which the "message" is written, the readers, writers, and erasers.
3. The origin of such complex communication systems is best explained by an intelligent designer. Since no humans were involved in creating these complex computing systems, a suprahuman super-intelligent agency must have been the creator.
The histone Information system is irreducibly complex
1. In living cells, information is encoded through the histone code which is a set of rules, stored in amino acid sequences in the histone tail. They are used to orchestrate gene expression. And so, the information which is sent through the system, as well as the communication channels that permit encoding, sending, and decoding, which in gene expression is done through the orchestration of histone code readers, writers, erasers, and permit the loosening and tightening chromatin, and in consequence, the RNA polymerase machinery to express specific genes.
2. A codified information transmission system depends on: a) A code as a system of rules where a symbol, letters, words, or even sounds, gestures, or images, are assigned to something else. Assigning meaning of characters through a code system requires a common agreement of meaning. Statistics, Semantics, Synthax, and Pragmatics, b) Information encoded through that code, c) An information storage system, and d) an information transmission system, that is encoding, transmitting, and decoding.This system had to be set-up all at once. That is the software - the histone code "language", as well as the hardware, that is the histone tails upon which the "message" is written, the readers, writers, and erasers.
3. The assignment of codified meaning to combinatorial amino acid sequences must be pre-established by a mind.The origin of such complex communication systems is best explained by an intelligent designer. Since no humans were involved in creating these complex computing systems, a suprahuman super-intelligent agency must have been the creator.
Loosening and tightening chromatin: Histones as gatekeepers
Histones are critical because they are responsible for either facilitating or forbidding gene expression.
Methyl groups condense nucleosomes more tightly, preventing access to promoter sites and thus preventing gene transcription. Acetylation loosens nucleosome packing, exposing the DNA to RNA polymerase II and transcription factors that will activate the genes.
Repression and activation are controlled to a large extent by modifying the “tails” of histones H3 and H4 with two small organic groups: methyl (CH3) and acetyl (COCH3) residues. In general, histone acetylation— the addition of negatively charged acetyl groups to histones—neutralizes the basic charge of lysine and loosens the histones, which activates transcription. Enzymes known as histone acetyltransferases place acetyl groups on histones (especially on lysines in H3 and H4), destabilizing the nucleosomes so that they come apart easily (become more euchromatic). As might be expected, then, enzymes that remove acetyl groups—histone deacetylases—stabilize the nucleosomes (which become more heterochromatic) and prevent transcription.
Histone methylation is the addition of methyl groups to histones by enzymes called histone methyltransferases. Although histone methylation more often results in heterochromatic states and transcriptional repression, it can also activate transcription depending on the amino acid being methylated and the presence of other methyl or acetyl groups in the vicinity. For instance, acetylation of the tails of H3 and H4 along with the addition of three methyl groups on the lysine at position four of H3 (i.e., H3K4me3; remember that K is the abbreviation for lysine) is usually associated with actively transcribed chromatin. In contrast, a combined lack of acetylation of the H3 and H4 tails and methylation of the lysine in the ninth position of H3 (H3K9) is usually associated with highly repressed chromatin. Indeed, lysine methylations at H3K9, H3K27, and H4K20 are often associated with highly repressed chromatin.
Histone methylations on histone H3.
The tail of histone H3 (its aminoterminal sequence, at the beginning of the protein) sticks out from the nucleosome and is capable of being methylated or acetylated. Here, lysines can be methylated and recognized by particular proteins. Methylated lysine residues at positions 4, 38, and 79 are associated with gene activation, whereas methylated lysines at positions 9 and 27 are associated with repression. The proteins binding these sites (not shown to scale) are represented above the methyl group.
Post-transcriptional modifications (PTMs) of histones affect gene transcription
This is certainly the most relevant epigenetic level of transcription regulation. In brief, histones have “tails” that can be modified by attaching various kinds of groups to them. So, each of the four histone types in the nucleosome (usually H2A, H2B, H3 and H4) can be methylated or polymethylated, acetylated, phosphorylated, ubiquitinated, sumoylated, biotinylated and many other things, at different amino acid sites, usually lysines or arginines. The combinatorial result is that more than 150 different histone PTMs have been described. However, methylations and acetylations are the most studied. Histone H3 is the most involved in current studies, and methylations and acetylations are the modifications that have been better analyzed.. The term “histone code” refers in a general way to the sum total of these different modifications and of their effects on chromatin state and transcription. However, many aspects of these complex processes are still poorly understood. In general, the best known PTMs are classified as having an effect of transcription activation or repression. Acetylations are mostly activating, methylation can be either activating or repressing. 43
The amino-terminal tails of histone proteins are subject to several types of covalent modifications. For example, an enzyme called histone acetyltransferase attaches acetyl groups (—COCH3) to the amino-terminal tails of histone proteins. When acetylated, histone proteins do not bind as tightly to the DNA, which aids in transcription. Over 50 different enzymes have been identified in mammals that selectively modify amino-terminal tails. The figure below shows an example in the amino-terminal tails of histone proteins H2A, H2B, H3, and H4 that can be modified by acetyl, methyl, and phosphate groups.
Indeed, lysine methylations at H3K9, H3K27, and H4K20 are often associated with highly repressed chromatin. The figure above depicts a nucleosome with lysine residues on its H3 tail. Modifications of such residues regulate transcription. If methyl groups at specific places on histones repress transcription, getting rid of these methyl moieties should be expected to permit transcription. That has been shown to be the case in the activation of the Hox genes, a family of genes that are critical in giving cells their identities along the anterior-posterior body axis. In early development, Hox genes are repressed by H3K27 trimethylation (the lysine at position 27 on histone
3 has three methyl groups: H3K27me3). In differentiated cells, however, a demethylase specific for H3K27me3 is recruited to these regions, eliminating the methyl groups and enabling access to the gene for transcription. The
effects of methylation in controlling gene transcription are extensive.
Examples of covalent modifications that occur to the amino terminal tails of histone proteins.
The amino acids are numbered from the N-terminus, or amino end. The modifications shown here are m for methylation, p for phosphorylation, and ac for acetylation. Many more modifications can occur to the amino terminal
tails. These modifications are reversible.
What are the effects of covalent modifications of histones? First, modifications may directly influence interactions between DNA and histone proteins, and between adjacent nucleosomes. The acetylation of histones loosens their binding to DNA and aids in transcription. Second, histone modifications provide binding sites that are recognized by other proteins.
The histone Code hypothesis
According to the histone code hypothesis, proposed by American biologists Brian Strahl and David Allis in 2000, the pattern of histone modification is recognized by proteins much like a language or code. One pattern of histone modification may attract proteins that inhibit transcription. Alternatively, a different combination of histone modifications may attract proteins, such as ATP-dependent chromatin-remodeling complexes, that promote gene transcription. In this way, the histone code plays a key role in accessing the information within the genomes of eukaryotic species.
The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar Modifications such as DNA methylation, it is part of the epigenetic code. Histones associate with DNA to form nucleosomes, which themselves bundle to form chromatin fibers, which in turn make up the more familiar chromosome. Histones are globular proteins with a flexible N-terminus (taken to be the tail) that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlates well to gene expression levels. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. 19
Combinations of histone modifications at a given position on the genome constitute the input system, the adaptors are the epigenetic regulators (for instance enzymatic complex Ezh2) that bind the modifications and outputs are chromatin features such as the level of chromatin compaction or gene expression 38 The histone modification sequence is orchestrated by the enzymes that either deposit, read or remove the marks, and serve as the adaptors molecules essential to biological codes. Enzymes that deposit marks are diverse and reflect the large spectrum of modifications available . Well-known examples are of histone acetyl-transferases (HAT) which transfer the acetyl group from acetyl-Coenzyme A to the tail of histones, and histone deacetylases (HDACs) which remove the acetyl groups, most notably upon chromatin compaction.
The impact of three primary histone modifications on chromatin compaction.
H3K4me3-rich nucleosomes are associated with active chromatin in an open conformation, H3K27me3-rich nucleosomes are associated with repressed chromatin, while H3K9me3-rich nucleosomes are associated with highly-compacted, inactive chromatin.
It has been half a century since Vincent Allfrey first described the presence of acetylation and methylation on histones, and Lubomir Hnilica documented histone phosphorylation, the functional significance of these modifications remained elusive for many years. Fundamental breakthroughs in our understanding of histone PTM function (many of which occurred in recent years) have been made through the identification of the protein machineries that incorporate (write), remove (erase), and bind (read) histone PTMs. Two landmark discoveries in this regard were the identifications in 1996 of p55/Gcn5 and HDAC1/Rpd3 as transcription-associated histone acetyltransferases and deacetylases, respectively — thereby linking dynamic histone modification activity directly to the transcription process. These findings changed the landscape of how the transcription and chromatin fields viewed histone PTMs and have resulted in a fast-paced and exciting field that shows no signs of slowing down. In 2000, the concept of a ‘histone code’ emerged as a hypothesis to stimulate new thinking about how histone PTMs might function, like through the selective recruitment of effector proteins or readers that ‘dock’ onto histone PTMs to direct specific downstream events in chromatin. While the ‘histone code’ hypothesis provided a retrospectively simplistic explanation of how histone PTMs function, recent advances have revealed that the context in which histone PTMs operate is much more complex than originally envisioned. 39
Post-translational modifications (PTMs) of histones provide a fine-tuned mechanism for regulating chromatin structure and dynamics. 36
In addition to combinatorial PTMs that function together both synergistically and antagonistically, there is now an appreciation for PTM asymmetry within individual nucleosomes, novel types of PTMs with unique functions, nucleosomes bearing histone variants, and nuclear compartmentalization events that are all contributing to the final output of chromatin organization and function.
Histone–DNA interface PTMs (in contrast to those located on the histone tail domains) largely act in a physical manner by tweaking or fine-tuning histone–DNA interactions that in turn affect nucleosome stability and/or mobility. While PTMs located at the histone–DNA interface regulate the intrinsic properties of the nucleosome core particle, it is noteworthy that these modifications can also regulate effector protein association similar to those located in the tail domains.
Posttranslational modifications (PTMs) on histones act singly and in combination to form a language or ‘code’ that is read by specialized proteins to facilitate downstream functions in chromatin. Underappreciated at the time this was discovered in the early-2000's was the level of complexity harbored both within histone PTMs and their combinations, as well as within the proteins that read and interpret the language. In addition to histone PTMs, newly-identified DNA modifications that can recruit specific effector proteins have raised further awareness that histone PTMs operate within a broader language of epigenetic modifications to orchestrate the dynamic functions associated with chromatin.
The hypothesis is that chromatin-DNA interactions are guided by combinations of histone modifications. While it is accepted that modifications (such as methylation, acetylation, ADP-ribosylation, ubiquitination, citrullination, and phosphorylation) to histone tails alter chromatin structure, a complete understanding of the precise mechanisms by which these alterations to histone tails influence DNA-histone interactions are to be figured out. However, some specific examples have been worked out in detail. For example, phosphorylation of serine residues 10 and 28 on histone H3 is a marker for chromosomal condensation. Similarly, the combination of phosphorylation of serine residue 10 and acetylation of a lysine residue 14 on histone H3 is a tell-tale sign of active transcription.
Histone post-translational modifications (PTMs) generate a complex combinatorial code that regulates gene expression and nuclear functions, and whose deregulation has been documented in different types of cancers.
25
This raises the question: How could such a combinatorial code have evolved, if regulation is a must, and deregulation is a source of cancer and cell death?
Functional Consequences of Histone Modifications
(A) Gene-expression changes are brought about by the recruitment of the NURF complex, which contains a component BRTF recognizing H3K4me and a component-remodeling chromatin.
(B) The Crb2 protein of fission yeast is recruited to DNA-repair foci during a DNA-repair response. Crb2 is partly tethered there by association with methylated H4 and phosphorylated H2A.
(C) The HBO1 acetyltransferase is an ING5-associated factor and is therefore tethered to sites of replication via methylated H3K4. HBO1 also binds to the MCM proteins found at replication sites. Evidence exists that HBO1 augments the formation of the preinitiation complex and is required for DNA replication.
About languages, codes, and libraries
A genomic library is a collection of the total genetic information stored in DNA from a single organism. The information in a library does no good to anyone unless the books are read. The same thing is true for DNA -- without being read, it doesn't do any good. So there are some obvious parallels between a library and a cell's DNA. Each gene could be compared to one assembly manual. Genes are organized in long strings, called chromosomes. If a gene is an assembly manual, then you can think of each chromosome as a shelf in a library. All the chromosomes together are like a library full of shelves. A nucleosome is like a shelf of the library, a basic unit of DNA packaging in eukaryotes, consisting of a segment of DNA wound in sequence around eight histone protein cores. Imagine the DNA strand equivalent to the book which carries the information. It is wrapped around these globular histone proteins which form a disk, but an N-terminal histone tail is like an arm that protrudes from the nucleosome, and on that tail, information can be modified, that is: a) written, b) read, or c) erased by specific enzymes. The enzymes that write on the tail are equivalent and perform the same job as to whom informs the computer where to find the book in the shelf, inform the proteins that afterward read the information what gene section is there ( the book in our analogy ) , and as well, when the DNA wrapped around the histones has to be expressed, or remain tightly bound to histones and the transcription machinery has no access, and it is as if the book remains in the Shelf without use. These chromatin-associated proteins dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states.
The combinatorial nature of histone amino-terminal modifications thus reveals a “histone code” that orchestrates and regulates gene expression. This epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
Epigenetics, imposed at the level of DNA-packaging proteins (histones), is a critical feature of a genome-wide mechanism of information storage and retrieval. Histone proteins and their associated covalent modifications contribute to a mechanism that can alter chromatin structure, thereby leading to inherited differences in transcriptional “on-off” states or to the stable propagation of chromosomes by defining a specialized higher order structure at centromeres.
The enzymes transducing these histone tail modifications are highly specific for particular amino acid positions.
Question: How could this specificity have emerged slowly, in a gradual evolutionary manner? Trial and error? and why would unguided, non-intelligent biochemical molecules even produce such specific, highly complex information storage and retrieval systems of other information?
Epigenetic “on-off ” transcriptional states are largely dependent on the position of a gene within an accessible (euchromatic) or an inaccessible (heterochromatic) chromatin environment.
a) The human language is an advanced information and communication system and must be determined by the common agreement of meaning of words and grammar in advance before any communication can take place, understood by both, sender and receiver.
b) Information transmitted through spoken words can be expressed in written words, that is, words and sentences are transformed into a codified communication form through codes or symbols, and a system of rules which function as representation, most commonly through writing systems, like the alphabet, or Kanji etc. In order for communication to occur, a mutual understanding, both, of a) the language, and b) of the code, by the sender, and the receiver is required. The transmission of codified information occurs through communication channels. It has to be a) written b) transmitted, c) read, and d) and eventually deleted or erased if so required. The codified information can also be stored in mediums, like ink/paper, or computer hard disks etc.
there has to be a common language understood by sender and receiver
a code system able to represent the language understood by sender and receiver
a sender/encoder that transmits the information based on the language, and rules of the code
a communication channel that transmits the information, and knows how to send the information to the right destination/address.
a receiver/decoder that receives the information and understands the code, and the language.
- if an English speaker visits a German website, it won't understand the information, even if its the same message written with the alphabet, because the language is different.
- if an English speaker that only knows the alphabet visits a Japanese website providing information in the English language, but using the Japanese Kanji symbols, he won't be able to decipher the message.
- If there is an extraordinary event taking place, but nobody writes about it and publishes, nobody else will know. ( No sender )
- If there is an extraordinary event taking place, and someone reports about it, but there is no internet access to publish the information on a site on the web, nobody will be able to read it. ( No communication channel )
- If there is someone elaborating a website and publishes it on the web, but nobody knows about it, nobody will take notice. ( No receiver/reader)
A library management program is necessary for the fast retrieval and return of books. The fast retrieval of information where to find a book in a library depends on the organized labeling of each library section, shelf, and eventually even the individual books, and is ordered in theme and genre sections, and every shelf has a tag which can be recognized and informs what books are there, and what themes. The books need first to be separated by genre and put together in categories. Then they have to be cataloged, one by one, before put together to the right shelf.
So there are two hierarchical information systems in the Cell, to name: the Histone Code, which is highly complex, and functions equivalent to a code to establish a program or language equivalent / similar to a computer-based management program of a library, used by specialized histone proteins to write on histone tails and inform the histone "reader" proteins when the DNA wrapped up in the nucleosomes has to be either keep mute and silenced, or has to be expressed by the transcription machinery, and when ( the right timing ). The information written by these proteins on these tails comes from multiple sources, and depends on the programmed timing of the gene regulatory network, the development program of the organism, responses coming from signals depending on environmental conditions, and responses to food sources, and homeostasis, responses depending on feedback loops as response to needs of synthesis of basic building molecules, amino acids, nucleotides, carbohydrates, fatty acids, metabolic and catabolic responses etc.
Readers, writers, editors, and erasers
Histone protein tails are critical for controlling gene expression: they are dynamically modified by post-translational modifications (PTMs) many of the modifications have been correlated with regulatory cellular processes and chromatin structure. 30 Most histone PTMs are localized on the N-terminal tail of the histone sequence. The structure of the nucleosome leaves the N-terminal tails of the histones exposed, allowing them to be readily accessed by members of histone-related protein families.
The histone code is written on histone tails by specific enzymes, called "writers or editors", which can write ( methylate or acetylate DNA ), but not exclusively, on the histone N-terminal tail or remove information by another kind of enzymes, called "erasers", which remove modifications and have demethylase or deacetylase activity, and finally, there are proteins which can interpret and read the information, called "readers" that are recruited to such histone modifications and bind via specific domains. READERS can bind specifically to the MARK and recruit a variety of other activities. These triple action of ‘writing’, ‘reading’ and ‘erasing’ establish the favorable local environment for transcriptional regulation. 29
Readers are usually not enzymes, but proteins containing domains that recognize specific modifications, potentially recruiting complexes like transcription factors or DNA repair machinery.
it is hard to assign functions to histone modifications is their combinatorial nature; a given PTM co-exists with myriad others on the same histone protein, and it is not rare for them to be found to cross-talk with one another.
The chemical nature of histones can also be changed at the protein sequence level, where the canonical histones used to package the majority of the genome are substituted by histone variants. Although many factors, such as linker histones and DNA-binding proteins, can influence characteristics such as DNA wrapping and fiber compaction, the greatest changes in nucleosome structure and stability are achieved by histone chaperones and ATP-dependent chromatin remodelers. Histone chaperones are highly acidic proteins that stabilize histones in the absence of DNA and thus play critical roles in nucleosome assembly and disassembly. Chromatin remodelers are essential for altering the composition and position of nucleosomes by coupling ATP hydrolysis to exchange of histone variants, nucleosome sliding, and octamer assembly/disassembly.
Nucleosomes must dynamically change so that DNA binding complexes can access their binding sites. These dynamic changes, which include nucleosome unwrapping, rewrapping, sliding, assembly, and disassembly, involve the formation and/or disruption of interactions within the interfaces between the DNA, H3/H4, and H2A/H2B components of the nucleosome.
In conjunction with histone variants, PTMs not only alter the intrinsic dynamics of nucleosomes but also provide chemical signposts to help guide cellular factors to particular locations in the genome.
During mitosis, phosphorylation of threonine 3, serine 10, and serine 28 disrupts the binding of READERS to methylation MARKS on lysines 4, 9, and 28, respectively. Thus, one MARK can regulate the activity of an adjacent MARK. Acetylation involves the transfer of acetate groups from acetyl coenzyme A to the ε-amino groups of lysine. This reduces the net positive charge of the N-terminal domain, causing chromatin to adopt an “open” conformation that is more favorable to transcription. The acetylation MARK acts as a binding site for protein READERs, one example of which is an approximately 100-amino-acid sequence motif called a bromodomain. Various bromodomain-containing READERS recruited to chromatin by acetylated histones often further modify histones in other ways that either promote or limit the accessibility of the DNA for transcription into RNA.
Proteins called transcription factors regulate gene expression by binding specific DNA sequences and recruiting the transcriptional machinery (RNA polymerases and associated proteins) to activate gene expression.
NETWORK OF INTERACTIONS THAT REGULATE RNA POLYMERASE II.
Input comes from transcription factors bound to promoter proximal elements and enhancers and from coregulators that modify chromatin.
Many transcription factors recruit a protein complex, called a coactivator, that facilitates loading of the transcriptional apparatus onto the gene. Often, coactivators possess domains that recognize histone MARKS and have EDITOR activities to lay down new MARKS on N-terminal histone tails. For example, the yeast SAGA complex contains over 10 proteins, including READERS that recognize histone methylation and acetylation. It also has an EDITOR activity that removes the protein MARK ubiquitin from target proteins plus a histone acetyltransferase EDITOR activity that acetylates lysine-14 and lysine-8 in the N-terminal tails of histone H3
Transcription factors (purple) bind specific DNA sequences and recruit coactivators to the 5′ ends of genes. Many of these coactivators work by acetylating the N-terminal tails or body of the core histones, thereby loosening the chromatin structure and promoting the binding and activation of the RNA polymerase holoenzyme. The coactivators vary in composition and complexity from relatively simple histone acetyltransferase complexes (bottom left) to the huge and elaborate SAGA complex (bottom right). In this side view, only one of the two turns of DNA around the nucleosome is seen. GCN5, Ada2, Ada3, Spt3, Spt7, Spt8, and Spt20 are the names of budding yeast genes whose products are found in these complexes. AC, acetylation; TATA, DNA sequence in the gene promoter
Histone acetylation is dynamic. Just as transcriptional coactivators contain histone acetyltransferases that add acetyl groups to nucleosomes and promote gene activation, so corepressors, which are recruited in an analogous manner, can contain histone deacetylases that remove acetyl groups from selected lysine residues. Deacetylation tends to repress gene expression and is one strategy used to regulate cell-cycle progression during the G1 phase of the cell cycle. Histone acetylation is crucial for life. Yeast cells die if certain key lysines are mutated to arginines, thus preserving their positive charge but preventing them from being acetylated. In addition to marking nucleosomes by modification of their N-terminal tails, cells also use the energy provided by adenosine triphosphate (ATP) hydrolysis to actively remodel nucleosomes. This involves complex protein “machines” that include a catalytic subunit that couples ATP hydrolysis to DNA translocation. All eukaryotes possess approximately 20 different classes of these chromatin remodeling enzymes. These different subclasses are capable of directing a range of different changes to nucleosome organization. For example, some enzymes reposition nucleosomes so that they are evenly spaced along DNA. Others remove histones from DNA. Still others direct replacement of core histone proteins with specialized variants.
Post-translational modifications (PTMs) of histones provide a fine-tuned mechanism for regulating chromatin structure and dynamics. PTMs can alter direct interactions between histones and DNA and serve as docking sites for protein effectors, or readers, of these PTMs. Binding of the readers recruits or stabilizes various components of the nuclear signaling machinery at specific genomic sites, mediating fundamental DNA-templated processes, including gene transcription and DNA recombination, replication and repair. 21 The nucleosomes undergo recurrent structural rearrangements through DNA unwrapping and rewrapping and histone core disassembly and assembly, and they are subject to covalent modifications. The modifications, or epigenetic marks, have been identified on both DNA and histones. Whereas DNA can primarily be methylated, histones are capable of carrying a wide array of PTMs. A particularly large number of PTMs have been discovered on the histone tails that protrude from the nucleosomal core and are freely accessible to enzymes for the deposition or removal of PTMs.
Readers of histone PTMs. Recognition of the methylated (me) lysine, methylated (me) arginine, acetylated (ac) lysine and phosphorylated (ph) serine and threonine residues of the N-terminal histone H3 tail by indicated readers.
HISTONE MODIFICATIONS.
A, E → M → R → C pathways use posttranslational modifications to create different chromatin states.
B, Modification of the amino- and carboxyterminal domains of the histones regulates nucleosome assembly, transcription, and mitotic chromosome condensation. Highlighted here are methylations of three lysines, which are associated with transcription, heterochromatin, and facultative heterochromatin respectively. Note that each residue is immediately adjacent to a residue phosphorylated in mitosis, which knocks the READER off the methylation mark. The modifications are described in the figure key.
C, Structure of tri-methyl lysine.
A schematic depiction of a nucleosome showing principal lysine methylation sites on histones H3 and H4. The reported writers (methyltransferases) and erasers (demethylases) for each lysine methylation are also depicted with their methylation state specificities: single circle (), me1; double circle (), me2; triple circle (), me3. 37
Covalent marks on chromatin 45
(a) Chromatin consists of repeated units of 146 bp of DNA wrapped 1.7 times around an octamer composed of two copies each of the four core histones; H2a, H2b, H3 and H4. Chromatin provides a structural platform that is subject to extensive post-translational modification. These include methylation, acetylation, phosphorylation and ubiquitination of specific histone residues; methylation of CpG dinucleotides; exchange of histones
(b) changes in the relative position of the nucleosome-mediated byATP-dependent remodelling complexes
(c) induction of double-stranded DNA breaks by topoisomerase II
(d) the generation of single-stranded DNA breaks by topoisomerase I
41
A structurally diverse family of histone reader domains has been discovered over the last decade, including bromodomains that bind acetyllysine, chromodomains that bind methyllysine, plant homeodomain (PHD) fingers that bind acetyllysine, methyllysine, and even unmodified lysine, Tudor domains that bind methyllysine and methylarginine, and BRCT domains that bind phosphoserine
1 https://en.wikipedia.org/wiki/Transcription_(biology)
2. Gene Regulatory Networks: Methods and Protocols [1 ed.] page 3
3. https://en.wikipedia.org/wiki/Transcriptional_regulation
4. https://en.wikipedia.org/wiki/Transcription_factor
5. https://en.wikipedia.org/wiki/Gene_regulatory_network
6. http://sci-hub.tw/https://www.cell.com/trends/genetics/abstract/S0168-9525(17)30070-7
7. https://pdfs.semanticscholar.org/presentation/12fc/722fe7ba63bdb7a7e6fe98d395840d0fe1cf.pdf
8. Gene Regulatory Networks, Methods and Protocols, page 3
9. A Handbook of Transcription Factors (Subcellular Biochemistry ) page 2
10. https://www.annualreviews.org/doi/abs/10.1146/annurev-genom-091212-153423
11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664230/
12. https://www.semanticscholar.org/paper/Movie-script-markup-language-Rijsselbergen-Keer/ff7e21d640d1ad6c7e5b44196153ea9e01db043c
13. http://sci-hub.tw/https://www.nature.com/articles/nrg2499
14. https://en.wikipedia.org/wiki/Regulation_of_gene_expression
15. https://www.ncbi.nlm.nih.gov/pubmed/10064544
15. https://upload.wikimedia.org/wikipedia/commons/1/17/Cell_Biology.pdf
16. http://wwf.panda.org/knowledge_hub/teacher_resources/webfieldtrips/hab_adaptation/
17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091299/
18. http://sci-hub.tw/https://www.nature.com/articles/nrg2540
19. https://en.wikipedia.org/wiki/Histone_code
20. http://sci-hub.tw/https://www.nature.com/articles/nsmb.2669
21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645987/
22. http://sci-hub.tw/https://www.ncbi.nlm.nih.gov/pubmed/10638745/
23. https://en.wikipedia.org/wiki/Histone
24. https://www.nature.com/scitable/topic/gene-expression-and-regulation-15
25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934616/
26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3193420/
27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380191/
28. Xhemalce B, Dawson MA, Bannister AJ. Histone modificationsIn: Meyers R, ed. Encyclopedia of Molecular Cell Biology and Molecular Medicine. John Wiley and Sons; 2011, page 419
29. https://en.wikipedia.org/wiki/Chromatin_remodeling
30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512434/
31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323801/
32. http://sci-hub.tw/https://www.nature.com/articles/s41586-018-0029-y
33. http://sci-hub.tw/https://www.ncbi.nlm.nih.gov/pubmed/29643506
34. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947954/
35. https://www.med.unc.edu/~bstrahl/Scott%20B.%20Rothbart%20&%20Brian%20D.%20Strahl.pdf
36. http://sci-hub.tw/https://www.nature.com/articles/nsmb.2436
37. https://www.nature.com/articles/emm201711
38. https://www.biorxiv.org/content/biorxiv/early/2017/11/20/217190.full.pdf
39. https://www.roswellpark.org/sites/default/files/tomasi_paper_2_rothbart_strahl_bba_2014_interpreting_the_language_of_histone_dna_modifications.pdf
40. https://www.quora.com/Why-does-DNA-methylation-and-histone-modifications-form-the-epigenetic-code
41. https://watermark.silverchair.com/gkw1011.pdf
42. https://docs.abcam.com/pdf/chromatin/a-guide-to-epigenetics.pdf
43. https://uncommondescent.com/intelligent-design/transcription-regulation-a-miracle-of-engineering/
44. http://sci-hub.tw/https://www.ncbi.nlm.nih.gov/pubmed/16751179
45. http://sci-hub.tw/https://www.ncbi.nlm.nih.gov/pubmed/18805503/
Histone modifications - the most significant reversible factors for cell differentiation and biodiversity
https://sciencerefutesevolution.blogspot.com/2018/11/histone-modifications-most-significant.html?fbclid=IwAR0kcyhvxBNf-BvF51qE1tpkdpiPL2SsYoY-MaHtnQbukEENn_WPw7BGOD8
Last edited by Otangelo on Fri Jun 18, 2021 7:44 am; edited 9 times in total
